Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD

Taskinen, Marja‐Riitta; Packard, Chris J.; Borén, Jan

doi:10.1007/s11883-019-0791-9

Cited by 79 publications

(56 citation statements)

References 112 publications

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“…However, this ASO was not approved by the FDA for the treatment of familial chylomicronemia syndrome due to adverse effects related to thrombocytopenia. The Committee for Medicinal Products for Human Use of the European Medicines Agency however, authorized conditional marketing for Waylivra (volanesorsen) as an adjunct to diet in adult patients with genetically confirmed familial chylomicronemia syndrome who are at high risk for pancreatitis, in whom response to diet and TG-lowering therapy has not worked (123). New formulations of APOC3 inhibitory drugs are likely to reduce side-effects.…”

Section: Emerging Strategies To Lower Hypertriglyceridemia and Theirmentioning

confidence: 99%

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Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Basu

Bornfeldt

2020

Front. Endocrinol.

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Human studies support a strong association between hypertriglyceridemia and atherosclerotic cardiovascular disease (CVD). However, whether a causal relationship exists between hypertriglyceridemia and increased CVD risk is still unclear. One plausible explanation for the difficulty establishing a clear causal role for hypertriglyceridemia in CVD risk is that lipolysis products of triglyceride-rich lipoproteins (TRLs), rather than the TRLs themselves, are the likely mediators of increased CVD risk. This hypothesis is supported by studies of rare mutations in humans resulting in impaired clearance of such lipolysis products (remnant lipoprotein particles; RLPs). Several animal models of hypertriglyceridemia support this hypothesis and have provided additional mechanistic understanding. Mice deficient in lipoprotein lipase (LPL), the major vascular enzyme responsible for TRL lipolysis and generation of RLPs, or its endothelial anchor GPIHBP1, are severely hypertriglyceridemic but develop only minimal atherosclerosis as compared with animal models deficient in apolipoprotein (APO) E, which is required to clear TRLs and RLPs. Likewise, animal models convincingly show that increased clearance of TRLs and RLPs by LPL activation (achieved by inhibition of APOC3, ANGPTL3, or ANGPTL4 action, or increased APOA5) results in protection from atherosclerosis. Mechanistic studies suggest that RLPs are more atherogenic than large TRLs because they more readily enter the artery wall, and because they are enriched in cholesterol relative to triglycerides, which promotes pro-atherogenic effects in lesional cells. Other mechanistic studies show that hepatic receptors (LDLR and LRP1) and APOE are critical for RLP clearance. Thus, studies in animal models have provided additional mechanistic insight and generally agree with the hypothesis that RLPs derived from TRLs are highly atherogenic whereas hypertriglyceridemia due to accumulation of very large TRLs in plasma is not markedly atherogenic in the absence of TRL lipolysis products.

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Section: Emerging Strategies To Lower Hypertriglyceridemia and Theirmentioning

confidence: 99%

“…Human studies have firmly linked APOC3 to plasma TG levels ( 121 – 123 ). APOC3 is mainly produced by the liver and to a lesser extent, by the intestine.…”

Section: Animal Models Of Hypertriglyceridemia and Their Susceptibilimentioning

confidence: 99%

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Basu

Bornfeldt

2020

Front. Endocrinol.

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“…Furthermore, recent studies suggest that apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of TRLs and their RLPs (14)(15)(16)(17)(18), predicts incident CVD in subjects with T1DM even when triglyceride levels are in the normal range or close to normal range (19,20). The effect of APOC3 as a CVD risk factor was independent of glycemic control (HbA1c levels).…”

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confidence: 99%

Monocytes and Macrophages as Protagonists in Vascular Complications of Diabetes

Kanter

Hsu

Bornfeldt

2020

Front. Cardiovasc. Med.

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With the increasing prevalence of diabetes worldwide, vascular complications of diabetes are also on the rise. Diabetes results in an increased risk of macrovascular complications, with atherosclerotic cardiovascular disease (CVD) being the leading cause of death in adults with diabetes. The exact mechanisms for how diabetes promotes CVD risk are still unclear, although it is evident that monocytes and macrophages are key players in all stages of atherosclerosis both in the absence and presence of diabetes, and that phenotypes of these cells are altered by the diabetic environment. Evidence suggests that at least five pro-atherogenic mechanisms involving monocytes and macrophages contribute to the accelerated atherosclerotic lesion progression and hampered lesion regression associated with diabetes. These changes include (1) increased monocyte recruitment to lesions; (2) increased inflammatory activation; (3) altered macrophage lipid accumulation and metabolism; (4) increased macrophage cell death; and (5) reduced efferocytosis. Monocyte and macrophage phenotypes and mechanisms have been revealed mostly by different animal models of diabetes. The roles of specific changes in monocytes and macrophages in humans with diabetes remain largely unknown. There is an ongoing debate on whether the changes in monocytes and macrophages are caused by altered glucose levels, insulin deficiency or insulin resistance, lipid abnormalities, or combinations of these factors. Current research in humans and mouse models suggests that reduced clearance of triglyceride-rich lipoproteins and their remnants is one important mechanism whereby diabetes adversely affects macrophages and promotes atherosclerosis and CVD risk. Although monocytes and macrophages readily respond to the diabetic environment and can be seen as protagonists in diabetes-accelerated atherosclerosis, they are likely not instigators of the increased CVD risk.

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“…Consistent with a critical role for apoC-III, genome-wide association studies have shown that loss-of-function (LOF) variants of this protein are associated with reduced plasma TG levels [7][8][9] . These observations suggest that inhibition of apoC-III function should be of therapeutic benefit and there is much interest in developing suitable approaches 10 . In particular, reduction of apoC-III expression using an antisense oligonucleotide 11,12 and direct protein targeting with a monoclonal antibody 13 show promise.…”

Section: Introductionmentioning

confidence: 99%

ApoC-III helical structure determines its ability to bind plasma lipoproteins and inhibit Lipoprotein Lipase-mediated triglyceride lipolysis

Vitali

Stankov

Khetarpal

et al. 2020

Preprint

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AbstractIn humans, apolipoprotein C-III (apoC-III) plasma levels have been associated with increased risk of cardiovascular disease. This association is in part explained by the effects of apoC-III on triglyceride (TG) metabolism; apoC-III raises plasma TG by increasing very low density lipoprotein (VLDL) secretion, inhibiting lipoprotein lipase (LPL)-mediated TG lipolysis, and impairing the removal of triglyceride-rich lipoprotein (TRL) remnants from the circulation. In this study, we explored the structure-function relationship the interaction of apoC-III with plasma lipoproteins and its ultimate impact on LPL activity. The structural and functional properties of wild-type (WT) apoC-III were compared with two missense variants previously associated with lower (A23T) and higher (Q38K) plasma TG. ApoC-III in the lipid-free state is unstructured but its helix content and stability increases when bound to lipid. Lipid-bound apoC-III contains two alpha helices spanning residues amino acids 11 - 38 (helix 1) and 44 – 64 (helix 2). Investigation of the structural and functional consequences of the A23T and Q38K variants showed that these amino acid substitutions within helix 1 do not significantly alter the stability of the helical structure but affect its hydrophilic-lipophilic properties. The A23T substitution impairs lipoprotein binding capacity, reduces LPL inhibition, and ultimately leads to lower plasma TG levels. Conversely, the Q to K substitution at position 38 enhances the lipid affinity of helix 1, increases TRL binding capacity and LPL inhibition, and is associated with hypertriglyceridemia. This study indicates that structural modifications that perturb the hydrophilic/lipophilic properties of the alpha helices can modulate the hypertriglyceridemic effects of apoC-III.

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Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD

Cited by 79 publications

References 112 publications

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Monocytes and Macrophages as Protagonists in Vascular Complications of Diabetes

ApoC-III helical structure determines its ability to bind plasma lipoproteins and inhibit Lipoprotein Lipase-mediated triglyceride lipolysis

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